The primary object of this proposal is to conduct a Phase II clinical trial testing a novel immunotherapy combination with programmed death protein 1 (PD-1) blockade, cryoablation, and intra-tumor injection of dendritic cell vaccines (DC) in non-Hodgkin lymphoma (NHL). NHL is the seventh most common type of cancer and one of the top ten causes of cancer deaths in United States. Patients with aggressive NHL continue to have poor survival with salvage treatments at the time of relapsed or refractory disease. Indolent NHL remains incurable, making less toxic but effective treatment an important part of therapy selection consideration. For both these considerations, immunotherapy has been one of the most exciting advances in the recent years. We have completed a Phase I study treating NHL patients with cryoablation and intra-tumor injections of autologous DC into the cryoablated tumors. This treatment was very well tolerated with no major adverse events. More importantly, abscopal systemic response was seen with this non-toxic, localized immunotherapy approach. Five of the 10 treated patients had partial response with an average time to progression of 64 weeks (range 51-80 weeks). Building on this promising approach, we have identified two deficiencies that can be targeted with PD-1 blockade: 1. DCs have increased PD-L1 (programmed death ligand-1) expressions that impairs their ability to prime CD8 T cell for antigen-specific responses; 2. Increased presence of a novel population of tumor-reactive CD8 T cells in the blood and tumors of lymphoma patients with decreased effector functions and capacity to differentiate into memory cells. We hypothesize that the combination of PD-1 blockade with monoclonal antibody Pembrolizumab (supplied by Merck), cryoablation and intra-tumor DC therapy will improve clinical efficacy through improved anti-lymphoma immunity through a combination of increased antigenic response, increased effector function and or decreased immunosuppressive phenotype. We have designed a Phase I/II study and secured funding for the Phase I portion of the study where the MTD of this combination will be determined. In this proposed study, we aim to complete the phase II portion of the study to determine the clinical efficacy and examine the immunity changes with this novel combination immunotherapy in NHL.